Cardioplegia refers to paralysis of the heart using chemicals. Typically this is effected in order to stop a heart during cardiac surgery. During cardiac surgery, the heart is subjected to an elective period of global ischaemia to provide the surgeon with a blood-free operating field and a still, flaccid heart. To protect the heart during ischaemia, a cardioplegic solution is used for rapid arrest and to help protect the heart from ischaemic injury.
Historically the heart used to be stopped in cardiac surgery by clamping the aorta, inducing ischaemia and cooling the heart down. This was called hypothermic ischaemic arrest. Hypothermic arrest led to an invariably lethal condition called the stone heart in up to one out of ten patients undergoing cardiac surgery.
Subsequently, a method of chemically inducing cardiac arrest was developed after decades of research. This ended the occurrence of the condition “stone heart” and made cardiac surgery a much safer procedure. The chemical arrest (cardioplegia) is induced by perfusing the heart with a cardioplegic solution containing moderately high concentrations of potassium (K) in addition to other electrolytes. One of these solutions, known as St. Thomas' Hospital (STH) cardioplegia, has been used as the predominant crystalloid cardioplegic solution world-wide since. STH is used widely in cardiac surgical centres, and relies on an increased potassium concentration to induce arrest; this has been shown to be reasonably effective and safe. However, potassium induces a ‘depolarised’ arrest that can be associated with increases in intracellular sodium and calcium concentrations; intracellular overload of these ions can be harmful to the heart.
St. Thomas' Hospital (STH) cardioplegia is relatively safe but it causes a shift in the resting membrane potential to a level that can have detrimental effects, such as increasing the intracellular sodium (Na) and calcium (Ca) concentrations. In order to induce arrest without shifting the resting membrane potential, relatively large amounts of pharmacological agents are usually, but not necessarily, required compared with changing the K concentration of the heart. Na channel and Ca channel blockers in addition to K channel openers are examples of these pharmacological agents. Considerable research has been conducted over the past 25 years where various pharmacological agents at high concentrations have been studied with variable outcomes. However these have not been translated to clinical studies due to the safety concerns, such as the slow washout of the agents from the body, which would lead to prolonged toxic effects.
Despite the remarkable improvement offered by St. Thomas' Hospital (STH) cardioplegia over hypothermic ischaemic arrest, it is well established that STH cardioplegia causes a shift in the resting membrane of the heart from about −85 mV to about −50 mV. This is thought to be detrimental because it causes Na and Ca loading which results in ischaemic contracture and poor recovery of the heart.
Chang et al (2002 Cardiology, volume 97, pages 138 to 146) disclose a study of interactions of esmolol and adenosine in atrioventricular nodal-dependent supraventricular tachycardia. Adenosine is known to operate via the direct effect on activation of the adenosine-sensitive potassium current. However, at the time, less was understood about the indirect effect of adenosine on antagonism of catecholamine-stimulated adenylate cyclase activity. Indeed, there were conflicting reports on this subject in the art at the time of this publication. In order to address this, Chang et al studied the beta-adrenergic blockade to determine whether or not it would potentiate the effects of adenosine. Thus, in the course of this study, low dose esmolol infusion was occasionally practised on a subject, and adenosine infusion was also practised on the same subject. This study was confined to the subject of tachycardia. Esmolol and adenosine were consistently treated as separate and non-overlapping reagents in addressing tachycardia in this study. Indeed, Chang et al conclude that esmolol pre-treatment did not produce any positive synergistic effect on the efficacy of adenosine-induced termination of supraventricular tachycardia. Thus, there is no disclosure towards using a dual esmolol/adenosine treatment. Furthermore, the subject matter of this publication is tachycardia. There is no disclosure in connection with cardioplegia in this document.
Bessho and Chambers (2000 Journal of Thoracic and Cardiovascular Surgery, volume 120, pages 528 to 537) disclose a study of intermittent cross-clamping with fibrillation and myocardial protection. In particular, this study investigated whether injury was reduced principally due to the shorter cumulative ischemic period, or whether there was in fact an intrinsic protective effect. This was a comprehensive study, which compared at least nine different regimes and perfusion protocols. For example, FIG. 1 on page 530 of this document summarises the range of regimes examined. The authors made numerous conclusions from this study, the most important being that equivalent levels of myocardial protection were achieved using either multidose cardioplegia, or using intermittent cross-clamping (with or without fibrillation). These findings allowed the authors to conclude that intrinsic preservation by intermittent cross-clamping with fibrillation did not exacerbate ischemic injury. Nowhere in this document is the use of esmolol disclosed. Nowhere in this document is the use of adenosine disclosed.
Bessho and Chambers (2001 Journal of Thoracic and Cardiovascular Surgery, volume 122, pages 993 to 1003) disclose the efficacy of esmolol as a cardioplegic agent. The authors had noticed that it was a common surgical practice to use intermittent cross-clamping with fibrillation as an alternative to cardioplegia during myocardial re-vascularisation. They were also aware that intermittent cross-clamping with fibrillation offered an intrinsic protection equivalent to the use of cardioplegia. Following on from these observations, the authors investigated whether arrest (rather than fibrillation) during intermittent cross-clamping might be beneficial. They also compared intermittent esmolol cardioplegia with global ischaemia. In the course of the study disclosed, the inventors compared arrest using esmolol only, arrest using the classic St Thomas' Hospital (STH) cardioplegia, and intermittent cross-clamp fibrillation (ICCF). The authors concluded that intermittent arrest with esmolol does not enhance protection of intermittent cross-clamping with fibrillation. However, multiple esmolol infusions during global ischemia did provide improved protection. Further conclusions were drawn from various comparisons between constant flow and constant pressure infusion. However, use of adenosine is not mentioned anywhere in this document. No combination of esmolol and adenosine is disclosed in this publication.
McCully (2002 Journal of Thoracic and Cardiovascular Surgery, volume 124, pages 219 to 220) discusses the use of oxygenated multidose delivery of crystalloid esmolol cardioplegia as an alternative to high potassium cardioplegia. The numerous different approaches taken in the art at that date are reviewed in this editorial. Furthermore, oxygenated multidose crystalloid esmolol cardioplegia is critically assessed for its provision of myocardial protection. It is concluded that esmolol cardioplegia might provide a useful alternative to a traditional high potassium depolarizing cardioplegia. Nowhere in this editorial is the use of adenosine disclosed.
Bessho and Chambers (2002 Journal of Thoracic and Cardiovascular Surgery, volume 124, pages 340 to 351) investigated myocardial protection using oxygenated esmolol cardioplegia during prolonged normothermic ischemia. This publication built on previous work which showed that multidose infusions of high dose esmolol provided excellent myocardial protection under normothermic global ischemia conditions. This publication specifically addressed the importance of oxygenation in achieving optimum protection. A robust comparative study was disclosed which compared the use of the St Thomas' Hospital (STH) cardioplegia together with oxygenated and un-oxygenated esmolol based cardioplegia. This study presented the important finding that oxygenated esmolol cardioplegia could completely protect the heart at certain timescales under normothermic global ischemia. This study clearly demonstrated that deoxygenated esmolol cardioplegia was significantly less protective, and that oxygenation of standard STH solution did not alter its protective efficacy under the conditions used. Related conclusions in the area of comparing constant pressure to constant flow infusion were also disclosed. In summary, this publication teaches the importance of oxygenation when using esmolol cardioplegia in order to obtain optimal myocardial protection. There is no disclosure of the use of adenosine anywhere in this document.
UK patent application number 0711805.2 was published as GB 2 436 255 A on 19 Sep. 2007. This document is concerned with organ preconditioning, arrest, protection, preservation and recovery. This document discloses compositions comprising anaesthetic, adenosine receptor agonist, and anti-adrenergic compounds. This document discloses extremely large numbers of potential individual identities of these generic components. For example, the adenosine receptor agonist is said to be selected from a list of several dozen alternatives. Myriad options are disclosed for the other elements of the composition. Amongst the wide range of different possible alternative ingredients for the compositions discussed, esmolol and adenosine are mentioned. In particular, page 30 lines 20 to 29, page 31 lines 1 to 2, and page 31 lines 14, 15 and 16 each disclose specific possible compositions which include both adenosine and esmolol. Firstly, it should be noted that this document discloses esmolol and adenosine as minor components of their composition. Furthermore, it is important to note that the concentrations of adenosine used, and particularly the concentrations of esmolol used, are very low. Moreover, it is important to understand the nature of the disclosure made in this document. This document is concerned with the use of anaesthetic such as lidocaine (sometimes referred to as lignocaine) as an arresting agent for induction of cardioplegia. Although the overall disclosure made in this document is at times obscure, for example in trying to reconcile the numerous divergent possible medical uses asserted for the compositions throughout the specification, and for example in trying to reconcile different elements of the disclosure which refer to different numbers of components in the compositions being described, and for example in trying to ascribe different functions to different components from the long lists presented, it is nevertheless clear that the only way in which arrest could be produced using the compositions disclosed is via the action of the anaesthetic component lidocaine. The function of the small amounts of esmolol and/or adenosine present in these compositions is limited to a protective effect. Lidocaine is toxic. Lidocaine has a long half-life in vivo of about 2 hours, and relies on the liver for clearance. The liver function can be compromised in cardiac surgery patients, which prolongs the lidocaine half-life even further. These factors can lead to dangerous build up of toxicity during lidocaine-induced cardioplegia. Anaesthetic such as lidocaine is an essential feature of the compositions disclosed in this document, as indicated in the abstract, the main claim, and throughout the description of the application. There is no disclosure in this document of the use of esmolol or adenosine as cardioplegic agents for the induction of arrest.
The present invention seeks to overcome problems associated with the prior art.